The present invention relates to tricyclic derivatives, to the pharmaceutical compositions containing them and to their use as phosphodiesterase 4 inhibitors.
Phosphodiesterases are a family of isoenzymes which constitute the basis of the main mechanism of cAMP (cyclic adenosine-3xe2x80x2,5xe2x80x2-monophosphate) hydrolytic inactivation. cAMP has been shown to be the second messenger mediating the biologic response to many of hormones, neurotransmitters and drugs [Krebs Endocrinology Proceedings of the 4th International Congress Excerpta Medica, 17-29, 1973]. When the suitable agonist binds to the cell surface, the adenylated cyclase activates and turns Mg2+-ATP into cAMP. cAMP modulates the activity of the majority, if not of all the cells contributing to the pathophysiology of various respiratory diseases, both of allergic origin and not. It follows that an increase of the cAMP concentration yields beneficial effects such as airway smooth muscle relaxation, inhibition of the mast cell mediator release (basophil granulose cells), suppression of the neutrophil and basophil degranulation, inhibition of the monocyte and macrophage activation. Thus, compounds able of activating adenylate cyclase or of inhibiting phosphodiesterases could suppress the undesired activation of the airway smooth muscle and of a great number of inflammatory cells.
In the phosphodiesterase family there is a distinct group of isoenzymes, phosphodiesterases 4 (hereinafter PDE 4) specific for the cAMP hydrolysis in the airway smooth muscle and inflammatory cells (Torphy, xe2x80x9cPhosphodiesterase Isoenzymes: Potential Targets for Novel Anti-asthmatic Agentsxe2x80x9d in New Drugs for Asthma, Barnes, ed. IBC Technical Services Ltd. 1989). Studies carried out on this enzyme show that its inhibition yields not only the airway smooth muscle relaxation, but also the suppression of mastocyte, basophil and neutrophil degranulation, so as the inhibition of the monocyte and neutrophil activation. In addition, the action of PDE 4 inhibitors is markedly strengthened when the adenylate cyclase activity of the target cells is increased by endogenous hormones, as it happens in vivo. Thus PDE 4 inhibitors are effective in the therapy of asthma. Such compounds offer a unique approach to the therapy of various respiratory diseases, both of allergic origin and not, and possess significant therapeutic advantages over the current therapy.
The excessive or irregular production of tumour necrosis factor (hereinafter TNFxcex1), a cytokine with pro-inflammatory activity produced by various kinds of cells, affects the mediation or the exacerbation of many pathologies such as, for example, the adult respiratory distress syndrome (ARDS) and the chronic pulmonary inflammatory disease. Therefore compounds able to control the negative effects of TNFxcex1, i.e. the inhibitors of this cytokine, are to be considered as useful against many pathologies.
The patent EP 0 526 840 (iKyowa Hakko Kogyo) claims compounds of formula 
wherein R1 is hydrogen, (C1-6)alkyl, (C7-15)arylalkyl or optionally substituted aryl; and R2 is hydrogen, (C1-6)alkyl, thienyl or optionally substituted aryl. These compounds are said to be active, inter alia, as antiinflammatories, immunosuppressives, bronchodilators.
The patent application JP 09227563 (Lederle Japan) describes compounds of formula 
wherein R is an optionally substituted amino group, Z is S or O, A and B form a benzene ring or are absent, and n is 0-2. These compounds are useful as bronchodilators, antiasthmatics, antihypertensives and anticholesterolemics.
The patent application WO 97/34893 (Astra) describes compounds of formula 
wherein B, D, E and G may form a benzene ring optionally substituted by alkoxy; X is Cxe2x95x90O, Cxe2x95x90S, Cxe2x95x90NR, CR3R6 or NR4; R3 is H or forms a bond with R2; R4 is lower alkyl or forms a bond with R2; R6 may be H, lower alkyl optionally substituted by phenyl, or cycloalkyl, phenyl, etc.; Y is N or CR; R2 may be H, lower alkyl optionally substituted by phenyl COOR, NRxe2x80x2Rxe2x80x3, OR, F, or cycloalkyl or may form a bond with one of R1, R3 and R4; R1 may be OH or lower alkyl or may form a bond with one of R2 and R5; R5 is a bond with R1 or R8; Z is OR8 or O; and Ar1 may be optionally substituted phenyl, pyridyl, pyrimidyl. These compounds have an antiinflammatory activity.
The patent application WO 98/09969 (Astra) describes compounds of formula 
wherein A, A1, A2 and A3 may be CH or CR4, X may be CH2 or O; Y may be a bond, CH2, Cxe2x95x90O, C substituted by alkyl in turn substituted by a cyclic residue; Z is a bond or CH2; R1 is hydrogen, lower alkyl or alkoxy; R2 and R3 are hydrogen or form a bond; and R4 may be optionally substituted alkoxy. These compounds have an antiinflammatory and antiallergic activity.
The patent application DE 19617862 (Schering AG) describes compounds of formula 
wherein, inter alia, R1 and R2 are H, alkyl, nitro, halogen, amino, lower alkoxy, CF3; R3 and R4 are H, alkyl, aryl, heteroaryl or cycloalkyl; Xxe2x95x90H; Y is alkoxy or X+Y=xe2x80x94Oxe2x80x94(CH2)nxe2x80x94Oxe2x80x94; n=1-3; and A is a 5-member heterocycle having from 1-3 nitrogen atoms. These compounds are inhibitors of glutamate receptor.
The patent application EP 0 548 923 (Takeda Chemical Ind.) describes, inter alia, compounds of formula 
wherein R1 is H or a lower alkyl group or a halogen atom; R4 and R5 are H or a lower alkyl group or form a 3-7 membered cycle optionally containing a heteroatom together with the carbon atom to which they are bound; A is an optionally substituted amino group: and m, n=1-4. These compounds are antiallergics, antiinflammatories and anti-PAF (anti-piastrinic activating factor), and are useful as antiasthmatics. In fact, these compounds act through an anti-PAF mechanism which makes them bronchodilators.
Similar compounds are claimed in the patent application EP 0 620 224 (Takeda Chemical Ind.) which illustrates, inter alia, the general formula 
wherein R1 is H or a lower alkyl group or a halogen atom; X is an oxygen or sulphur atom or a xe2x80x94CH2xe2x80x94 group; Y is a group 
wherein R4 and R5 are H or a lower alkyl group, or is a 3-7 membered cycle optionally containing a heteroatom; R6 and R7 are H, an optionally substituted lower alkyl, cycloalkyl or aryl or together with the nitrogen atom to which they are bound form a heterocycle, and m, n=0-4. These compounds have the same activity claimed in the just above cited patent application.
The patent application WO 98/21208 (Byk Gulden Lomberg) claims PDE3 and PDE4 inhibitors of formula 
wherein, inter alia, R1 is an alkyl group; R2 and R3 are hydroxy, optionally fluorinated alkoxy, cycloalkoxy and cycloalkylmethoxy; and R4 is a phenyl group substituted by carboxy, amido or alkoxycarbonyl and optionally substituted by halogen, alkyl, CF3, nitro or hydroxy. These compounds are said to be useful in the treatment of pathologies of the airways and/or of dermatosis.
It has now surprisingly been found a new class of phthalazine derivatives able to inhibit PDE 4 and TNFxcex1.
Therefore the present invention relates to compounds of formula 
wherein
A is a 5-7 membered heterocycle containing from 1 to 4 nitrogen atoms, optionally partially or totally unsaturated, and optionally substituted by a (C1-4)alkyl group in turn optionally substituted;
Z is NH, methylene, a C2-6 alkylene chain optionally branched and/or unsaturated and/or interrupted by a C5-7 cycloalkyl residue;
Cy is phenyl or heterocycle optionally substituted by one or more substituents, or a COR4 group wherein R4 is hydroxy, alkoxy, amino optionally substituted by one or two (C1-6)alkyl groups or by hydroxy;
R is a (C1-6)alkyl or polyfluoro(C1-6)alkyl group;
R1 is hydrogen; a (C1-8)-alkyl, (C2-8)-alkenyl or (C2-8)-alkynyl group optionally substituted by hydroxy, oxo, aryl or heterocycle, and optionally interrupted by one or more heteroatoms or heterogroups; a (C1-4)alkoxy group or a (C4-7)cycloalkoxy group optionally containing an oxygen atom and optionally substituted by a polar substituent in the cyclic moiety, aryloxy, aryl-(C1-10)-alkoxy;
the Nxe2x86x92O derivatives of the compounds of formula I and the pharmaceutically acceptable salts thereof.
Preferred compounds according to the invention are those of formula I wherein Z is methylene or a C2-6 alkylene chain.
Still more preferred compounds according to the invention are those of formula I wherein Z is methylene or a C2-6 alkylene chain; and Cy is a heterocycle optionally substituted by one or more substituents.
Still more preferred compounds according to the invention are those of formula I wherein Z is methylene; and Cy is pyridine substituted by two substituents.
The compounds of formula I can have one or more asymmetric centres and therefore they can be in the form of stereoisomers. Object of the present invention are compounds of formula I in the form of diastereoisomeric mixtures as well as of single stereoisomers.
The compounds of formula I are active as PDE 4 and TNFxcex1 inhibitors and thus are used as therapeutic agents in allergic and inflammatory pathologies such as, for example, emphysema, chronic bronchitis, asthma and allergic rhinitis.
For substituent Cy, as heterocycle it is particularly meant pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, piperazine, triazine, morpholine, pyrrolidine, pyrroline, imidazoline, pyrazoline, pyrazolidine, imidazolidine, piperidine, furan, pyran, isothiazole, isoxazole, thiophene and the like.
The optionally present substituents can be oxo, nitro, carboxy, halogen, that means a fluorine, chlorine, bromine or iodine atom. As xe2x80x9cpolar substituentxe2x80x9d they are meant those groups made by atoms having a different electronegativity, so forming a dipole, such as, for example, a hydroxy or keto group.
Specific examples of alkyl groups are methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, 1-methyl-butyl, 2-ethyl-propyl, 3-methyl-butyl, 3-methyl-2-butyl, n-hexyl, heptyl, octyl and the like; examples of substituents optionally present on the alkyl groups are (C1-6)alkoxy groups and amino groups mono- or di-substituted by (C1-4)alkyl groups.
As (C4-7)cycloalkyl group cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl are meant, while the aryl and the aryl moiety of the aryl-(C1-10)alkyl substituent mean an aromatic ring of 6-10 carbon atoms such as, for example, phenyl, naphthyl, indanyl, and the like, and, consequently, as aryl-(C1-10)-alkyl substituent, benzyl, phenylethyl, phenyl-pentyl, indanyl-pentyl and the like.
The oxidised form Nxe2x86x92O, when present, can be on the nitrogen atoms of the phthalazine ring as well as on those on Cy.
Pharmaceutically acceptable salts of the compounds of formula I are those with organic and inorganic acids, such as, for example, hydrochloric, hydrobromic, hydroiodic, sulfulric, phosphoric, nitric, acetic, benzoic, maleic, fumaric, succinic, tartaric, citric, aspartic, methanesulfonic and 3,7-di-t.butylnaphthalen-1,5-disulfonic (dibudinic acid), or with inorganic bases such as, for example, sodium or potassium hydroxide, sodium bicarbonate.
The synthesis of the compounds of formula I proceeds according to methods known to the skilled in the art. For example, when a compound of formula I wherein Z is different from NH is desired, the synthesis can start from an acid of formula 
wherein R and R1 are as above defined, which by reaction with formaldehyde/HCl gives a compound of formula 
wherein R and R1 are as above defined. This is oxidised, for example, with benzoyl peroxide/N-bromo-succinimide, and then hydrolysed to give a compound of formula 
wherein R and R1 are as above defined, which is treated with a hydrohalogenidric acid (HX) and triphenylphosphine to give a compound of formula 
wherein R and R1 are as above defined. This compound can be also obtained from compound III by radicalic halogenation with, for example, azaisobutyronitrile or benzoyl peroxide/N-bromo- or chloro-succinimide to give the compound of formula 
wherein R and R1 are as above defined, and X is chlorine or bromine, which gives compound V by treatment with triphenylphosphine.
Compound V is treated with an aldheyde of formula
Cyxe2x80x94Zxe2x80x3xe2x80x94CHOxe2x80x83xe2x80x83(VI)
wherein Cy is as above defined and Zxe2x80x3 is a C1-5 alkylene chain optionally branched and/or unsaturated and/or interrupted by a C5-7 cycloalkyl residue, or it is absent, in the presence of an organic base such as, for example, triethylamine, and gives a compound of formula 
wherein R, R1, Zxe2x80x3 and Cy are as above defined. This is reacted with hydrazine to give a compound of formula 
wherein R, R1, and Cy are as above defined and Z has the meanings reported in formula I but amino, which is treated with a halogenating agent, such as phosphoryl chloride or bromide, to give a compound of formula 
wherein R, R1 and Cy are as above defined, X is chlorine or bromine, and Z is different from amino, which is treated with a suitable nucleophile such as, for example, sodium azide or sodium tetrazolate, or with hydrazine and then with a suitable acylating agent such as, for example, acetic anhydride or acetyl chloride, and gives the desired compound of formula I.
The synthesis of the N-oxides of the compounds of formula I occurs by treating the compounds of formula I with peracids such as, for example, m-chloroperbenzoic acid.
The preparation of the salts of the compounds of formula I is carried out according to conventional methods.
The compounds of formula I are PDE 4 inhibitors as showed by the in vitro enzymatic inhibition tests (example 18), and furthermore are able to inhibit the TNFxcex1 release.
It is apparent how these enzymatic selectivity and specificity features combined with the lack of activity on the cardiovascular system make the compounds of formula I specifically suitable for treating pathologies involving PDE 4 and TNFxcex1 even if in the present context the interest is particularly focused on the respiratory pathologies. In particular the compounds of the invention are useful for treating allergic and inflammatory diseases and above all for treating emphysema chronic obstructive pulmonary disease (COPD) and chronic bronchitis specifically, asthma and allergic rhinithis.
The therapeutic doses shall be generally from 0.1 to 1.000 mg a day and from 1 to 100 mg by oral route for single administration.
A further object of the present invention are the pharmaceutical compositions containing a therapeutically effective amount of the compounds of formula I or pharmaceutically acceptable salts thereof in admixture with a suitable carrier.
The pharmaceutical compositions object of the invention can be liquid, suitable for the enteral or parenteral administration, and, preferably, solid such as tablets, capsules, granulates, suitable for the oral administration, or in a form suitable for the transdermal and inhalatory administration.
The preparation of the pharmaceutical compositions object of the invention can be carried out according to common techniques.